16, 17-disubstituted progesterones



United States Patent Ofifice 3,019,219 Patented Jan. 30, 1962 Thisinvention relates to substituted progesterones. More particularly, itrelates to l6a-methyl-l7m-lower alkanoyloxy-progesterones andderivatives thereof. 7

The new steroids of the present invention have the following generalformula:

Ol Ce wherein R is a member of the group consisting of hydrogen andlower alkanoyl radicals, and

s 4- 5- 6- is a member of the group consisting of:

The compounds of the present invention are, in genacetic anhydride, to

eral, white crystalline high melting (above 175 C.) solids relativelyinsoluble in water but soluble in lower alkyl alcohols, acetone, ethylacetate, tetrahydrofuran, benzene, toluene, methylene chloride and thelike.

The process to prepare the compounds of the present invention uses asstarting material, for example, Bfl-hydroxy 16a methyl-S-pregnen-ZO-one.The starting material is benzoylated by reaction with benzoyl chlorideor benzoic anhydride in pyridine to produce 3fl-benzoyloxy-16a-methy15-pregnen-20-one. This latter steroid is then reacted with alower alkanoic acid anhydride, preferably produce a3fl-benzoyloxy-20-lower alkanoyloxy 16a methyl-5,l7(20) pregnadiene.Alternately, the starting material, 3 8-hydroxy-l6u-methyl-5-pregnen-ZO-One, can be reacted with a'lower alkanoic acid anhydride,preferably acetic anhydride, to produce a 3B-20-dilower alkanoyloxy-l6amethyl-5,17(20) -pregnadiene.

The intermediate, 3B-benzoyloxy-20-loweralkanoylox'y-l6e-methyl-5,17(20)-pregnadiene (IV) or 35,20-diloweralkanoyloxy 16a methyl-5,17(20)-pregnadiene (III), is then oxidized withperbenzoic acid, treated with alkali to rearrange the epoxy ester and.treated with benzoyl chloride or acetic anhydride to insure that the 3-position is esterified. The alkaline treatment may deesterify the3-position thereby necessitating re-esterification as indicated.

When carrying out the reaction described immediately above, a mixture isobtained which can be separated by means of partition chromatography asshown in the examples. The desired fraction 6 consisting primarily of3[3-b6l'lZOylOXy-50L,60t-p0Xy 17a hydroxy-lfia-methyl pregnan-ZO-one(V). The latter compound is treated with a reducing agent such aslithium aluminum hydride to produce 3 3,50,17a,2O3-tetrahydroxy-16a-methylpregnane (VI). The latter compound is convertedinto a, 1704 dihydroxy-l6a-methylpregnane-3,205dione (VII) by treatmentwith an oxidizing agent, for example, such as N-bromosuccinimide,N-bromophthalimide, N-bromoacetamide and the like followed by treatmentwith acid or alkali to strip the elements of water creating the4,5-double bond. The resulting 17a-hydroxy-l6a-methyl-4-pregnene-3,20-dione (VIII) may be acylated by the use of loweralkanoic acid chlorides or anhydrides. The reactions described above canbe graphically illustrated by the following flowsheet which shows thespecific reactions.

in which 'R is a lower alkanoyl radical.

Compounds such as l7a-acetoxy-l6a-methyl progesterones have been foundto have progestational activity. Compounds of this activiy are useful invarious disorders such as, for example, habitual abortion, menopausalsyndrome and infertility. Steroids having progestational activity havealso been employed in prostatic carcinoma, acne vulgaris and senility.These compounds can be dispensed in the usual pharmaceutical forms suchas tablets, capsules, pills and the like. Obviously, they can becombined with fillers, diluents, excipients and other nontherapeuticcompounds necessary to the formulation of the pharmaceutical product.

The following examples illustrate in detail the preparation of thesubstituted progesterones of the present invention.

Example I 7 chloride solutions. The mixture is dried overnight over 100g. of anhydrous sodium sulfate, decanted from the drying agent, andevaporated under reduced pressure to a black viscous mass. The latter isdissolved in 300 ml. of benzene and diluted with 4 liters of petroleumether. The solution is filtered through 1000 g. of activated magnesiumsilicate and the column is washed with 4.2 liters of petroleumether:benzene (20:1) and 4 liters of henzene. The combined eluate onevaporation gives 72.9 g. of the crude product,3,3,20-diacetoxy-lGot-methyI-S, 17(20)-pregnadiene (II), a viscousorange oil whose in frared spectrum in carbon tetrachloride shows thepresence of only trace amounts of unreacted -20 ketone.

To a stirring solution of the crude enolacetate obtained above (72.9grams) in 1 liter of methylene chloride at C. is added 1105 ml. of a0.35 M solution of perbenzoic acid in benzene dropwise over 25 minutes.The resulting mixture is allowed to stand at 5 C. for 23 hours to give3fi,20-diacetoxy-5a,6u;l7a,20-diepoxy-16amethylpregnane (III). Themixture is diluted with 1.5 liters of ether and is washed successivelywith 5% sodium hydroxide, water and saturated sodium chloride solutions.The extract is concentrated to a viscous amber oil which is dissolved in600 ml. of hot ethanol and cooled to room temperature and 2400 ml. of 5%aqueousethanolic potassium hydroxide solution (150 g. sodium hydroxide,300 ml. of water and 2700 ml. absolute ethanol) is added. The resultingsolution is allowed to stand at room temperature for one hour and isthen neutralized with 160 ml. of glacial acetic acid. The reactionmixture is concentrated to a solid mass under reduced pressure andpartitioned between water and 1.5- 2.0 liters of ether methylenechloride (2:1). The extract is washed repeatedly with 5% sodiumhydroxide, water and saturated sodium chloride solution and isconcentrated to a semi-crystalline mass under reduced pressure whichcontains 511,60: epoxy-319,17 dihydroxy-16amethylpregnan-ZO-one (IV). Toa solution of the latter in 350 ml. of pyridine is added 27.9 g. ofbenzoyl chloride. The reaction mixture is allowed to stand 80 hours atroom temperature following which 50 ml. of water is added and theresulting mixture is stirred at room temperature for three hours. Themixture is then diluted with 3 liters of water and the amorphousprecipitates which formed is filtered and then dissolved in 2.5 litersof benzene-methylene chloride (ca 4:1). The extract is worked up in theusual way to give a yellow semicrystalline solid which is driedovernight under reduced pressureat 75 C. to give 69.9 grams. A portionof the crude mixture (15.0 grams) is partitioned over diatomaceous earthwith n-heptane-methylcellosolve to give the following results.

Frac. No.2

1-Very small amount of oil 2-Very small amount of oil 3-Very smallamount of oil 4-1.20 g. of colorless granules 5--0.58 g. of an amber gum6-2.37 g. of colorless crystals 72.68 g. of semi-crystalline solid 80.90g. of a semi-crystalline solid 9-4.82 g. of colorless semi-crystallinesolid Methanol wash of column-0.85 g. of a brown oily solid3fl-Benzoyloxy 5a,6a epoxy-17a-hydroxy-16a-methylpregnan-ZO-one (V) iscontained in Fraction No. 6. An analytically pure sample melts at 247.5-248.5 C.

Example [I PREPARATION OF 3.15.1.1maoe-Tnrnmnnoxx-rtoe METHYLPREGNANE Amixture containing 1.00 grams of 3fl-benzoyloxy-5u,6a-epoxy-17a-hydroxy-16u methylpregnan-ZO-one (prepared in Example I)and 0.830 grams of lithium aluminum hydride in 100 ml. oftetrahydrofuran (freshly distilled oii lithium aluminum hydride) is:heated to reflux for 17 hours. The mixture is cooled to roomtemperature, and the excess hydride is decomposed via the dropwiseaddition of water with cooling. The reaction mixture is partitionedbetween 15% sulfuric acid and ethyl acetate-benzene (1:1). The organicphase is washed successively with 5% potassium hydroxide-water andsaturated sodium chloride solutions, and on concentration gives acrystalline mass which crystallized from ethyl acetate to give 0.504grams (64% of theoretical yield) of3,8,5a,l7a,20}8-tetrahydroxy-16a-methylpregnane (VI) as colorlessprisms, melting point 216.5--222.5 C. An analytically pure sample has amelting point of 216- 219.5 C.

Example III PREPARATION OF 17 a-HYDROXY-16a-METHYL- PROGESTERONE To asolution containing 830 mg. of 3e,5a,17e,20,8-tetrahydroxy-l6a-methylpregnane (VI) in ml. of acetone is added 25 ml.of water and 1.57 grams of N-bromoacetamide. After the reaction hasstood for 17 hours at room temperature, it is diluted with 300 ml. ofwater and extracted repeatedly with ether. The ether extract is washedwith water and saturated sodium chloride solution and is evaporated to asemi-crystalline solid containing 5u,17a dihydroxy 16ozmethylpregnane-3,20-dione (VII) which is taken up in 60 ml. of methanoland heated to reflux with 6 ml. of a 5% aqueous potassium hydroxide forone hour under nitrogen. The reaction mixture is neutralized With aceticacid and evaporated to an amber gum which is taken up in a few ml. ofmethylene chloride and placed on a 40 gram column of activated magnesiumsilicate. The product, 17u-hydroxy-l6a-methylprogesterone (VIII), iseluted with 5% acetone-petroleum ether and crystallized from the samesolvents to give 263 mg. (34% of theoretical) of colorless prisms,melting point 178182.5 C. A sample recrystallized several times from theabove solvents has a melting point of l80- 183.5; [a] =-|-85.7.

Example IV PREPARATION OF 17tl-ACETOXY-16Cl-METHYL- PROGESTERON E To asolution containing 113 mg. of 17a-hydroxy-16amethylprogesterone (VIII)in 5.0 ml. of glacial acetic acid is added 111 mg. of p-toluenesulfonicacid (monohydrate) and 1.0 ml. of acetic anhydride. The mixture isallowed to stand for 60 hours at room temperature after which it isdiluted with ml. of water and the product is extracted into ether. Theether extract after washing with water and saturated sodium chloridesolution is evaporated to an amber oil. The latter is taken up in amixture composed of 20 ml. of methanol and 3.3 ml. of tetrahydrofuran.The resulting solution is cooled to 0 and 6.7 ml. of an ice coldsolution of 2% potassium hydroxide in methanol is added. After an hourat 0", the mixture is neutralized with dilute hydrochloric acid andevapo rated under reduced pressure to an amber gum. The productcontaining 1704 acetoxy-l6a-methylprogesterone (IX) is extracted intomethylene chloride and the extract is dried over anhydrous sodiumsulfate and concentrated to a small volume. The dried extract is placedon a small column of activated magnesium silicate (8 mm. x 22 cm.;60/100 mesh.), and the product is eluted with 3% acetone-petroleumether. Crystallization from acetone-petroleum ether gives 37 mg. ofcolorless needle clusters, melting point 210-231 C. A samplerecrystallized several times from the same solvents gives pure17e-acetoxyl6u-methylprogesterone (IX) with a melting point of 231-236C. (Kofier block).

In another experiment, mg. of 17a-hydroxy-16u- References Cited in thefile of this. patent UNITED STATES PATENTS 1' 2,878,247 Miramontes eta1. M i 17, .1959

OTHER REFERENCES Turne J.A.C.S. 75 (1953 a es34s9-92Q Fieser et :11.:Steroids, 1959, pages 200, 224 and 779. Reinhold Pub. Co., New York.

7 methylprogesterqne (VIII) is acefylated ford-v6 hour to give 39 mg. ofthe acetate (IX), melting point 229-234" C. ,(Kofier block). 7

We claim; 4 V V W 1. The compound 3B-benzoy1oxy 504,60-epoxy-17xhydroxy-16a-methylpregnan-20-one.

'2. The compound 5a,17a-dihydroxy-lm-methylpregnane-LZO-dione.

1. THE COMPOUND 3B-BENZOYLOXY - 5A,6A -EPOXY-17AHYDROXY-16A-METHYLPREGNAN-20-ONE
 2. THE COMPOUND5A,17A-DIHYDROXY-16A-METHYLPREGNANE-3,20-DIONE.